Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(=O)C.[CH:38](=O)[CH2:39][CH3:40].C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][N:22]([CH2:38][CH2:39][CH3:40])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CNCC4)cc2)cn1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1CCc2nc(Nc3ccc(-c4cnn(C)c4)cc3)nc(N(CCO)c3ccccc3)c2C1
Yield: 17.5 %

Procedure:
2-((2-(4-(1-Methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol, Example 38a) was dissolved in methanol (2 mL). Acetic acid (1.037 μL, 0.02 mmol) was added followed by propionaldehyde (0.013 mL, 0.18 mmol). The reaction mixture was stirred for 30 minutes at room temperature before sodium cyanoborohydride (11.39 mg, 0.18 mmol) was added. The solvent was evaporated under reduced pressure, the crude dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 2-((2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-6-propyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (7.6 mg, 15.4%) as acetic acid salt.
Reaction SMILES: CC1[CH:15]=[C:14]2[C:5]([S:6](=[O:23])(=[O:22])[C:7]3[CH:8]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O.[O-2].[O-2].[O-2].[Cr+6]>[C:29]([C:30]1[CH:3]=[CH:4][C:5]2[S:6](=[O:23])(=[O:22])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:8]=3)[C:13](=[O:16])[C:14]=2[CH:15]=1)([OH:32])=[O:31]
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Reaction time: 16 h

Procedure:
7-Methyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide (0,78g) was suspended in acetic acid (50 ml) and chromium trioxide (0.98g) in water (2.0 ml) added dropwise, followed by concentrated sulphuric acid (0.5 ml) added dropwise. The mixture was heated on the steam bath for 1 hr., then boiled under reflux for 4 hr. Further chromium trioxide (0.98g) was added and the mixture boiled for a further 16 hr. The green solution was diluted with water, and the precipitated solid filtered off and washed with water. The solid was boiled with acetic acid (200 ml), filtering at the boil.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (120 mg, 0.27 mmol) in dichloromethane (2 mL). After 1 h, the mixture was concentrated and saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 346.1 (M+1).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]=1[C:19]([O:21]C)=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28].O>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[NH:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[C:19](=[O:21])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:3]2=[O:23])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C

Procedure:
Diusopropylethylamine (3.20 g, 25 mmol) was added to a stirred suspension of methyl-3-[(t-butoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (8.00 g, 25 mmol) and aminoglutarimide hydrochloride (4.07 g, 25 mmol) in DMF (60 ml). The mixture was heated to 120° C. for 24 hours and then cooled to room temperature. The mixture was poured into cold water (300 ml) and extracted with ethyl acetate (4×100 ml each). The combined ethyl acetate extracts were washed with water (2×50 ml), brine (50 ml) and dried. Solvent was removed in vacuo and the product purified by flash chromatography (dichloromethane/ethyl acetate 8 to 2) to yield 4.66 g of recovered starting material and 3.31 g (82%) of the product as a white solid: mp 180–182° C.; 1H NMR (CDCl3) δ 8.51 (s, 1H), 7.81–7.67 (m, 3H), 5.54 (b, 1H), 5.03–4.96 (dd, J=5.2 and 11.2 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.95–2.74 (m, 3H), 2.18–2.14 (m, 1H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 170.99, 168.08, 167.95, 167.07, 155.86, 139.17, 135.00, 134.61, 132.15, 128.22, 122.82, 79.81, 49.21, 40.53, 31.33, 28.32, 22.58; Anal. Calcd for C19H21N3O6: C, 58.91; H, 5.46; N, 10.85. Found: C, 59.08; H, 5.51; N, 10.69.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCOC(=O)c1cn([C@H]2CCCNC2)c2cnc(Br)cc2c1=O
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn([C@H]2CCCN(CCN(CC)CC)C2)c2cnc(Br)cc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (5)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate hydrochloride (Intermediate 62, 610 mg, 1.46 mmol, 1 equiv.) in acetonitrile (4 mL) was added 2-chloro-N,N-diethylethanamine hydrochloride (252 mg, 1.46 mmol, 1 equiv.) followed by potassium carbonate (1 g, 7.32 mmol, 5 equiv.). This was stirred in the microwave at 120° C. for 30 min. The reaction was cooled to room temperature and diluted with ethyl acetate. The precipitate was discarded, and the filtrate was concentrated to provide (S)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate as a solid (mg, %).
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[C:7]([CH2:9][CH2:10][C:11](O)=[O:12])=O>O>[OH:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[C:7]1[CH2:9][CH2:10][C:11](=[O:12])[NH:2][N:3]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccccc1O
Solvent: O
Product: O=C1CCC(c2ccccc2O)=NN1

Procedure:
Hydrazine hydrate (1.2 ml) was added to a stirred suspension of 3-(2-hydroxybenzoyl)propionic acid (3.1 g) in water (20 ml), and the mixture was heated under reflux for 3/4 hour. The mixture was diluted with an equal volume of water, allowed to cool, and filtered to give 6-(2-hydroxyphenyl)-4,5-dihydro-3(2H)pyridazinone (2.6 g) m.p. 211°-212°.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([CH:31]([NH2:33])[CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:33][CH:31]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH3:32])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CC(N)c1cccc2ccccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(C)c2cccc3ccccc23)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-naphthalen-1-yl-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H25NO5 [M+H]+: 408.
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.[NH2:9][C:10]1[C:11]([I:28])=[C:12]([C:21]([NH:23][CH2:24][CH:25]([OH:27])[CH3:26])=[O:22])[C:13]([I:20])=[C:14]([C:18]=1[I:19])[C:15]([OH:17])=[O:16].CC(N(C)C)=O>O>[OH:4][CH2:5][C:6]([NH:9][C:10]1[C:11]([I:28])=[C:12]([C:21]([NH:23][CH2:24][CH:25]([OH:27])[CH3:26])=[O:22])[C:13]([I:20])=[C:14]([C:18]=1[I:19])[C:15]([OH:17])=[O:16])=[O:7]
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(O)CNC(=O)c1c(I)c(NC(=O)CO)c(I)c(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At temperatures no higher than 10° C., 13.3 ml. of acetoxyacetyl chloride is gradually added dropwise with agitation to a solution of 30.8 g. (50 mmol) of 5-amino-(2-hydroxypropyl)-2,4,6-triiodoisophthalamic acid in 60 ml. of dimethylacetamide. After 16 hours of agitation at room temperature and the addition of 10 ml. of water, the mixture is stirred for 30 minutes at room temperature and then concentrated under vacuum. The residue, after having been treated repeatedly with fresh water, is saponified on a steam bath with agitation with 70 ml. of 2N sodium hydroxide solution in 250 ml. of water. After cooling, the reaction mixture is acidified with 12.5 ml. of concentrated hydrochloric acid, stirred for 16 hours at room temperature, and, after adding approximately the same volume of saturated NaCl solution, allowed to stand for 4 days. Thereafter, the mixture is vacuum-filtered from the thus-separated precipitate, which is washed with minimum portions of water and dried under vacuum. Yield: 17.2 g. (51%), m.p. 275°-277° C., with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]([CH2:14][CH2:15][CH2:16][Cl:17])([C:12]#N)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:19].N.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CO.CCOCC>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH2:1]([N:8]1[CH2:11][C:10]([CH2:14][CH2:15][CH2:16][Cl:17])([C:12]([O:26][CH3:25])=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(CCCCl)CN(Cc2ccccc2)C1
Agent: N
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1(CCCCl)CN(Cc2ccccc2)C1
Temperature: 80 °C

Procedure:
A stirred solution of 1-benzyl-3-(3-chloropropyl)-azetidine-3-carbonitrile (D1, 5.35 g, 0.022 mole) in methanol (75 ml) was treated cautiously with 18 concentrated sulphuric acid (15 ml) and then heated at 80° C. for 20 h. The solution was cooled in an ice bath and a further 12 ml of concentrated sulphuric acid added. The solution was heated at 80° C. for a further 9 hours, then allowed to cool, before pouring cautiously into ice/water (400 ml) with vigorous stirring. The aqueous mixture was basified by the addition of 0.88 ammonia solution, then extracted with ethyl acetate (2×200 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave an orange oil, which was filtered through a basic alumina column eluting with ether. The colourless oil obtained was dissolved in ether (150 ml) and treated with a solution of oxalic acid (2.0 g, 0.022 mole) in methanol (10 ml). The title compound (D2) was filtered off as a white crystalline solid (7.25 g, 91%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:24])[CH2:22][Cl:23])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH3:24])[CH2:22][Cl:23])=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(CCl)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
440 parts by weight of nitrating acid, consisting of 200 parts by weight of concentrated nitric acid and 240 parts by weight of concentrated sulfuric acid, are added dropwise to 448 parts by weight of 3-(p-tert.-butyl-phenyl)-2-methyl-propyl chloride, whilst cooling with ice. After stirring has been continued for 3 hours at room temperature, the crude product is poured onto ice and extracted with diethyl ether, the extract is washed with water, with aqueous NaHCO3 solution and again with water and is dried over Na2SO4, the solvent is evaporated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[CH:19]=1>C(O)C.Cl>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:11][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)[CH:3]=1)(=[O:10])=[O:9]
Reactant: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2cccc(S(=O)(=O)NCCN(C)C)c2)c2ccccc2n1
Yield: 3.2 %

Procedure:
N-(2-Dimethylamino-ethyl)-3-nitro-benzenesulfonamide (3). To a solution of 3-nitrobenzenesulfonyl chloride (1, 1.0 g, 4.51 mmol) in anhydrous CH2Cl2 (9.0 mL) was added N,N-dimethyl-ethylenediamine (2, 0.5 mL, 4.55 mmol) dropwise. The resulting solution was stirred at room temperature overnight before it was diluted with EtOAc (80 mL). The organic mixture was washed with saturated NaHCO3 (90 mL), brine (90 mL), and dried over MgSO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 3 as a foam (0.8 g) which was used in the next step without further purification. Step 2. 3-Amino-N-(2-dimethylamino-ethyl)-benzenesulfonamide (4). A solution of 3 (0.8 g) in ethanol (10 mL) was subjected to catalytic hydrogenation (10% Pd/C, Degussa, 0.8 g, 3 drops of AcOH, 1 atm.) overnight. To work up, the solids were filtered the filtrate was dried under vacuum to afford 4 as a solid (0.71 g) which was used in the next step without further purification. Step 3. N-(2-Dimethylamino-ethyl)-3-(2-methyl-quinolin-4-ylamino)-benzenesulfonamide. To a solution of 4 (0.3 g, 1.23 mmol) and 4-chloroquinaldine (5, 0.26 mL, 1.29 mmol) in ethanol (10 mL) were added 2 drops of conc. HCl. The resulting mixture was heated under reflux overnight before ethanol was removed under reduced pressure. The residue was basified with saturated NaHCO3 (aq. 20 mL) and the basic solution was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, the solids were filtered and the filtrate was concentrated on a rotavap. The residue was purified on Florisil® to give the title compound as an orange solid (15 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH2:20])[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]([CH2:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH:20][C:37](=[O:38])[CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12

Procedure:
The crude methyl 3-benzyl-7-amino-3-cephem-4-carboxylate was dissolved in dry dichloromethane (3 ml.) and the solution cooled to -20°. Dry triethylamine (22 mg) in dichloromethane (0.5 ml) was added followed by phenoxyacetyl chloride (36 mg) in dichloromethane (0.5 ml). After 15 minutes the solution was washed with water (× 2), dried and evaporated. Chromatography on silica afforded methyl 3-benzyl-7-phenoxyacetamido-3-cephem-4-carboxylate (II) as a white solid (61 mg). A sample recrystallised from ethyl acetate/60°-80° petroleum ether had m.p. 161°-162°. νmax (Nujol) 3215, 1775, 1718, 1670, 1625 cm-1. δ ppm (CDCl3) 3.27 (AB quartet, J= 19Hz), 3.83 (AB quartet, J= 15 Hz), 3.9 (s, 3H), 4.57 (s, 2H), 5.03 (d, 1H, J= 5Hz), 5.88 (q, 1H, J= 5Hz, 10Hz), 6.8-7-5 (m, 11H).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]2[CH:19]=[N:20][CH:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)(O)=O.S(N)([NH2:25])(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>S1(CCCC1)(=O)=O>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]2[CH:19]=[N:20][CH:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)#[N:25]
Reactant: NS(N)(=O)=O
Reactant: O=C(O)CCCCCc1cccc2cncn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: N#CCCCCCc1cccc2cncn12
Temperature: 0 °C

Procedure:
Thionyl chloride (11.42 g) is added slowly at room temperature to a suspension of 5-(5-carboxypentyl)imidazo[1,5-a]pyridine (21.0 g) and sulfamide (10.5 g) in 90 ml of sulfolane. The mixture is heated at 120° until gas evolution ceases and solid p-toluenesulfonic acid monohydrate (1.71 g) is added carefully. After heating an additional 3 hours at 120°, the reaction mixture is cooled, poured onto 200 g of ice and acidified with 130 ml of 1N hydrochloric acid. The aqueous phase is sequentially extracted with ethyl acetate (3×100 ml), made basic with solid sodium bicarbonate and reextracted with ethyl acetate (3×125 ml). The organic extracts are washed with 0.5N sodium hydroxide (5×50 ml), dried over sodium sulfate and evaporated to yield an oil which is chromatographed on 60 g of silica gel with ethyl acetate to yield 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][C@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[C:18]([CH3:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (36 mg, yield 77%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:32](=[O:33])[CH2:31][O:30][C:29]5[CH:35]=[CH:36][C:26]([Cl:25])=[CH:27][CH:28]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCc2nc3c(N4CCNCC4)ncnc3s2)cc1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: O=C(COc1ccc(Cl)cc1)N1CCN(c2ncnc3sc(CCc4ccc(F)cc4)nc23)CC1
Yield: 48 %

Procedure:
This compound was prepared from 2-(4-fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].NC1C=CC=CC=1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]2[C:3]=1[NH:4][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]2=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)c(F)c1
Solvent: Nc1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(F)cc(OC)cc2c1=O
Yield: 77 %

Procedure:
A mixture of aniline 2-fluoro-4-(methoxy)aniline (22.8 g, 162 mmol) and diethyl [(ethyloxy)methylidene]propanedioate (32.6 mL) were heated to reflux in Dowtherm A under a flow of argon. After 15 minutes (when all ethanol was removed), the mixture was allowed to cool down and was diluted with pentane. A precipitate was formed which was triturated with pentane, filtered and dried under vacuum to afford the product as an oil (33.06 g, 77%); MS (+ve ion electrospray) m/z 265 (M+H)+.
Reaction SMILES: [CH3:1]I.C[Mg]I.[Br:6][C:7]1[CH:18]=[CH:17][C:10]([C:11](N(OC)C)=[O:12])=[C:9]([F:19])[CH:8]=1>C(OCC)C.O1CCCC1>[Br:6][C:7]1[CH:18]=[CH:17][C:10]([C:11](=[O:12])[CH3:1])=[C:9]([F:19])[CH:8]=1
Reactant: CI
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Agent: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
Into a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Mg (6 g, 250.00 mmol, 2.60 equiv) in diethyl ether (50 mL). To the resulting mixture was then added a solution of CH3I (118.4 g, 833.80 mmol, 7.80 equiv) in diethyl ether (75 mL) dropwise with stirring at room temperature. The resulting solution was allowed to react for 1 hr at room temperature. The above methylmagnesium iodide solution (2M) was then added to a solution of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (25 g, 95.42 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) dropwise with stirring at −20° C. The resulting solution was stirred for an additional 2 h at room temperature. The resulting mixture was cooled to 0° C. with a water/ice bath. The reaction was then quenched by the addition of NH4Cl/H2O (300 mL). The resulting solution was extracted with ethyl acetate (2×200 ml) and the organic layers combined. The resulting mixture was washed with water (1×200 mL) and brine (1×200 mL). The resulting mixture was dried over NaSO4 and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:PE (1:20) to yield 1-(4-bromo-2-fluorophenyl)ethanone as colorless oil.